PT  - JOURNAL ARTICLE
AU  - M.S. Bolhuis
AU  - R. van Altena
AU  - D. van Soolingen
AU  - W.C.M. de Lange
AU  - D.R.A. Uges
AU  - T.S. van der Werf
AU  - J.G.W. Kosterink
AU  - J.W.C Alffenaar
TI  - Clarithromycin increases linezolid exposure in multidrug-resistant tuberculosis patients
AID  - 10.1183/09031936.00001913
DP  - 2013 Jan 01
TA  - European Respiratory Journal
PG  - erj00019-2013
4099  - http://erj.ersjournals.com/content/early/2013/03/20/09031936.00001913.short
4100  - http://erj.ersjournals.com/content/early/2013/03/20/09031936.00001913.full
AB  - The use of linezolid for the treatment of multidrug-resistant tuberculosis is limited by dose- and time-dependent toxicity. Recently, we reported a case of pharmacokinetic drug-drug interaction between linezolid and clarithromycin resulting in increased linezolid exposure. The aim of this prospective pharmacokinetic study is to quantify the effect of clarithromycin on the exposure of linezolid.Subjects were included in an open-label, single-center, 1-arm, fixed-order pharmacokinetic interaction study. All subjects received 300 mg linezolid twice daily during the entire study, consecutively co-administered with 250 mg and 500 mg clarithromycin once daily. Steady-state serum curves of linezolid and clarithromycin were analysed using validated methods and differences between pharmacokinetic parameters were calculated.Linezolid exposure increased by a median of 44% (interquartile range: 23–102%, P=0.043) after co-administration of 500 mg clarithromycin (n=5) compared to baseline, whereas 250 mg clarithromycin had no statistically significant effect. Co-administration was well tolerated by most patients: none experienced severe adverse effects. One patient reported Common Toxicity Criteria Grade 2 gastro-intestinal adverse events.In this study, we showed that clarithromycin significantly increased linezolid serum exposure after combining clarithromycin with linezolid in multidrug-resistant tuberculosis patients. The drug-drug interaction is possibly P-glycoprotein mediated. Due to large inter-patient variability, therapeutic drug monitoring is advisable to determine individual effect size.